Clinical, Translational and Basic Research on Liver Diseases, 2nd Volume

Topic Information

Dear Colleagues,

Personalized medicine is a new approach to liver disease management. Liver research over the last decade has shown that response to therapy is variable, hence personalization and identifying factors that will enhance the predictive utility of targeted therapy are critical. There are assays such as the lymphocyte toxicity assay which can identify the hypersensitivity of an individual to drug use or misuse. The knowledge of drug adverse events can save lives and reduce health care costs dramatically. Biomarkers can help identify liver diseases. Cancer immunotherapy, which aims to control the immune system to eradicate cancer, needs to be personalized, because anticancer immune responses can be inhibited in various ways from patient to patient. Cancer immunotherapy includes immune checkpoint inhibitors and monoclonal antibodies, as well as cell therapy, immunogene therapy, and vaccines. Combinations of programmed apoptosis protein 1 (PD-1)/ligand 1 (PD-L1) chemotherapy and radiation therapy, are being explored. Biomarkers are important for predicting the response to immunotherapy in hepatocellular and cholangiocarcinomas. Molecular diagnostics and immunohistochemistry are important technologies for guiding treatment of liver diseases.

The scope of the present Topic is to present the need for:

• The identification of molecular targets as predictive biomarkers is important for matched targeted therapy in alcoholic and non-alcoholic steatohepatitis.
• Constant evaluation of assays to predict and diagnose drug-induced liver injury (DILI).
• Integration of viral-induced liver diseases as a possible co-morbidity of alcohol and drug misuse in liver disease laboratory diagnosis.
• Validation of biomarkers to predict response to combination therapies, including those that characterize the tumor microenvironment and targeted signaling pathways in carcinoma of the liver.

Prof. Dr. Neuman Manuela
Prof. Dr. Stephen Malnick
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biology biology	3.6	5.7	2012	16.1 Days	CHF 2700
Biomedicines biomedicines	3.9	5.2	2013	15.3 Days	CHF 2600
Current Issues in Molecular Biology cimb	2.8	2.9	1999	16.8 Days	CHF 2200
Diagnostics diagnostics	3.0	4.7	2011	20.5 Days	CHF 2600
International Journal of Molecular Sciences ijms	4.9	8.1	2000	18.1 Days	CHF 2900

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Published Papers (9 papers)

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9 pages, 764 KiB  

Open AccessArticle

Regeneration of Non-Alcoholic Fatty Liver Cells Using Chimeric FGF21/HGFR: A Novel Therapeutic Approach

by Sung-Jun Kim, So-Jung Kim, Jeongeun Hyun, Hae-Won Kim and Jun-Hyeog Jang

Int. J. Mol. Sci. 2024, 25(6), 3092; https://doi.org/10.3390/ijms25063092 - 7 Mar 2024

Viewed by 1750

Abstract

Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant liver ailment attributed to factors like obesity and diabetes. While ongoing research explores treatments for NAFLD, further investigation is imperative to address this escalating health concern. NAFLD manifests as hepatic steatosis, precipitating insulin [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant liver ailment attributed to factors like obesity and diabetes. While ongoing research explores treatments for NAFLD, further investigation is imperative to address this escalating health concern. NAFLD manifests as hepatic steatosis, precipitating insulin resistance and metabolic syndrome. This study aims to validate the regenerative potential of chimeric fibroblast growth factor 21 (FGF21) and Hepatocyte Growth Factor Receptor (HGFR) in NAFLD-afflicted liver cells. AML12, a murine hepatocyte cell line, was utilized to gauge the regenerative effects of chimeric FGF21/HGFR expression. Polysaccharide accumulation was affirmed through Periodic acid–Schiff (PAS) staining, while LDL uptake was microscopically observed with labeled LDL. The expression of FGF21/HGFR and NAFLD markers was analyzed by mRNA analysis with RT-PCR, which showed a decreased expression in acetyl-CoA carboxylase 1 (ACC1) and sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) with increased expression of hepatocellular growth factor (HGF), hepatocellular nuclear factor 4 alpha (HNF4A), and albumin (ALB). These findings affirm the hepato-regenerative properties of chimeric FGF21/HGFR within AML12 cells, opening novel avenues for therapeutic exploration in NAFLD. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases, 2nd Volume)

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13 pages, 834 KiB  

Open AccessReview

Interferon-Free Regimens and Direct-Acting Antiviral Agents for Delta Hepatitis: Are We There Yet?

by Roxana Nemteanu, Andreea Clim, Corina Elena Hincu, Liliana Gheorghe, Irina Ciortescu and Alina Plesa

Curr. Issues Mol. Biol. 2023, 45(10), 7878-7890; https://doi.org/10.3390/cimb45100498 - 28 Sep 2023

Cited by 1 | Viewed by 1717

Abstract

Chronic delta hepatitis is a global health problem. Although a smaller percentage of chronic HBV-infected patients are coinfected with the hepatitis delta virus, these patients have a higher risk of an accelerated progression to fulminant “delta hepatitis”, cirrhosis, hepatic decompensation, and hepatocellular carcinoma, [...] Read more.

Chronic delta hepatitis is a global health problem. Although a smaller percentage of chronic HBV-infected patients are coinfected with the hepatitis delta virus, these patients have a higher risk of an accelerated progression to fulminant “delta hepatitis”, cirrhosis, hepatic decompensation, and hepatocellular carcinoma, putting a financial strain on the healthcare system and increasing the need for a liver transplant. Since its discovery, tremendous efforts have been directed toward understanding the intricate pathogenic mechanisms, discovering the complex viral replication process, the essential replicative intermediates, and cell division-mediated viral spread, which enables virion viability. The consideration of the interaction between HBV and HDV is crucial in the process of developing novel pharmaceuticals. Until just recently, interferon-based therapy was the only treatment available worldwide. This review aims to present the recent advancements in understanding the life cycle of HDV, which have consequently facilitated the development of innovative drug classes. Additionally, we will examine the antiviral strategies currently in phases II and III of development, including bulevirtide (an entry inhibitor), lonafarnib (a prenylation inhibitor), and REP 2139 (an HBsAg release inhibitor). Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases, 2nd Volume)

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22 pages, 50235 KiB  

Open AccessArticle

Large HBV Surface Protein-Induced Unfolded Protein Response Dynamically Regulates p27 Degradation in Hepatocellular Carcinoma Progression

by Yixiao Guo, Jie Shao, Renyu Zhang, Mingwei Han, Lingmin Kong, Zekun Liu, Hao Li, Ding Wei, Meng Lu, Shuai Zhang, Cong Zhang, Haolin Wei, Zhinan Chen and Huijie Bian

Int. J. Mol. Sci. 2023, 24(18), 13825; https://doi.org/10.3390/ijms241813825 - 7 Sep 2023

Cited by 1 | Viewed by 1583

Abstract

Up to 50% of hepatocellular carcinoma (HCC) is caused by hepatitis B virus (HBV) infection, and the surface protein of HBV is essential for the progression of HBV-related HCC. The expression of large HBV surface antigen (LHB) is presented in HBV-associated HCC tissues [...] Read more.

Up to 50% of hepatocellular carcinoma (HCC) is caused by hepatitis B virus (HBV) infection, and the surface protein of HBV is essential for the progression of HBV-related HCC. The expression of large HBV surface antigen (LHB) is presented in HBV-associated HCC tissues and is significantly associated with the development of HCC. Gene set enrichment analysis revealed that LHB overexpression regulates the cell cycle process. Excess LHB in HCC cells induced chronic endoplasmic reticulum (ER) stress and was significantly correlated with tumor growth in vivo. Cell cycle analysis showed that cell cycle progression from G1 to S phase was greatly enhanced in vitro. We identified intensive crosstalk between ER stress and cell cycle progression in HCC. As an important regulator of the G1/S checkpoint, p27 was transcriptionally upregulated by transcription factors ATF4 and XBP1s, downstream of the unfolded protein response pathway. Moreover, LHB-induced ER stress promoted internal ribosome-entry-site-mediated selective translation of p27, and E3 ubiquitin ligase HRD1-mediated p27 ubiquitination and degradation. Ultimately, the decrease in p27 protein levels reduced G1/S arrest and promoted the progress of HCC by regulating the cell cycle. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases, 2nd Volume)

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15 pages, 1163 KiB  

Open AccessReview

The Intestinal Microbiome and the Metabolic Syndrome—How Its Manipulation May Affect Metabolic-Associated Fatty Liver Disease (MAFLD)

by Stephen D. H. Malnick and Sheral Ohayon Michael

Curr. Issues Mol. Biol. 2023, 45(9), 7197-7211; https://doi.org/10.3390/cimb45090455 - 31 Aug 2023

Cited by 5 | Viewed by 2037

Abstract

Metabolic-associated fatty liver disease (MAFLD) is now the predominant liver disease worldwide consequent to the epidemic of obesity. The intestinal microbiome (IM), consisting of the bacteria, fungi, archaea, and viruses residing in the gastrointestinal tract, plays an important role in human metabolism and [...] Read more.

Metabolic-associated fatty liver disease (MAFLD) is now the predominant liver disease worldwide consequent to the epidemic of obesity. The intestinal microbiome (IM), consisting of the bacteria, fungi, archaea, and viruses residing in the gastrointestinal tract, plays an important role in human metabolism and preserving the epithelial barrier function. Disturbances in the IM have been shown to influence the development and progression of MAFLD and play a role in the development of metabolic syndrome (MS). The main treatment for MAFLD involves lifestyle changes, which also influence the IM. Manipulation of the IM by fecal microbial transplantation (FMT) has been approved for the treatment of recurrent Closteroides difficile infection. This may be administered by endoscopic administration from the lower or upper GI tract. Other methods of administration include nasogastric tube, enema, and oral capsules of stool from healthy donors. In this narrative review, we elaborate on the role of the IM in developing MS and MAFLD and on the current experience with IM modulation by FMT on MAFLD. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases, 2nd Volume)

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20 pages, 11320 KiB  

Open AccessArticle

Targeting Endothelial Necroptosis Disrupts Profibrotic Endothelial–Hepatic Stellate Cells Crosstalk to Alleviate Liver Fibrosis in Nonalcoholic Steatohepatitis

by Mengli Yan, Hui Li, Shiyu Xu, Jinyan Wu, Jiachen Li, Chengju Xiao, Chunheng Mo and Bi-Sen Ding

Int. J. Mol. Sci. 2023, 24(14), 11313; https://doi.org/10.3390/ijms241411313 - 11 Jul 2023

Cited by 9 | Viewed by 1999

Abstract

Chronic liver diseases affect over a billion people worldwide and often lead to fibrosis. Nonalcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes, is characterized by liver fibrosis, and its pathogenesis remains largely unknown, with no effective treatment available. Necroptosis [...] Read more.

Chronic liver diseases affect over a billion people worldwide and often lead to fibrosis. Nonalcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes, is characterized by liver fibrosis, and its pathogenesis remains largely unknown, with no effective treatment available. Necroptosis has been implicated in liver fibrosis pathogenesis. However, there is a lack of research on necroptosis specific to certain cell types, particularly the vascular system, in the context of liver fibrosis and NASH. Here, we employed a mouse model of NASH in combination with inducible gene knockout mice to investigate the role of endothelial necroptosis in NASH progression. We found that endothelial cell (EC)-specific knockout of mixed lineage kinase domain-like protein (MLKL), a critical executioner involved in the disruption of cell membranes during necroptosis, alleviated liver fibrosis in the mouse NASH model. Mechanistically, EC-specific deletion of Mlkl mitigated the activation of TGFβ/Smad 2/3 pathway, disrupting the pro-fibrotic crosstalk between endothelial cells and hepatic stellate cells (HSCs). Our findings highlight endothelial MLKL as a promising molecular target for developing therapeutic interventions for NASH. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases, 2nd Volume)

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19 pages, 6869 KiB  

Open AccessArticle

Impact of Gut Recolonization on Liver Regeneration: Hepatic Matrisome Gene Expression after Partial Hepatectomy in Mice

by Abdul Rahman Amin, Ngatiman M. Hairulhisyam, Raman Nur Fatin Aqilah, Mohd Manzor Nur Fariha, Beth L. Mallard, Fergus Shanahan, Antony M. Wheatley and Muhamad Marlini

Int. J. Mol. Sci. 2023, 24(13), 10774; https://doi.org/10.3390/ijms241310774 - 28 Jun 2023

Cited by 1 | Viewed by 1482

Abstract

The hepatic matrisome is involved in the remodeling phase of liver regeneration. As the gut microbiota has been implicated in liver regeneration, we investigated its role in liver regeneration focusing on gene expression of the hepatic matrisome after partial hepatectomy (PHx) in germ-free [...] Read more.

The hepatic matrisome is involved in the remodeling phase of liver regeneration. As the gut microbiota has been implicated in liver regeneration, we investigated its role in liver regeneration focusing on gene expression of the hepatic matrisome after partial hepatectomy (PHx) in germ-free (GF) mice, and in GF mice reconstituted with normal gut microbiota (XGF). Liver mass restoration, hepatocyte proliferation, and immune response were assessed following 70% PHx. Hepatic matrisome and collagen gene expression were also analyzed. Reduced liver weight/body weight ratio, mitotic count, and hepatocyte proliferative index at 72 h post PHx in GF mice were preceded by reduced expression of cytokine receptor genes Tnfrsf1a and Il6ra, and Hgf gene at 3 h post PHx. In XGF mice, these indices were significantly higher than in GF mice, and similar to that of control mice, indicating normal liver regeneration. Differentially expressed genes (DEGs) of the matrisome were lower in GF compared to XGF mice at both 3 h and 72 h post PHx. GF mice also demonstrated lower collagen expression, with significantly lower expression of Col1a1, Col1a2, Col5a1, and Col6a2 compared to WT mice at 72 h post PHx. In conclusion, enhanced liver regeneration and matrisome expression in XGF mice suggests that interaction of the gut microbiota and matrisome may play a significant role in the regulation of hepatic remodeling during the regenerative process. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases, 2nd Volume)

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15 pages, 350 KiB  

Open AccessReview

Preclinical Models and Promising Pharmacotherapeutic Strategies in Liver Fibrosis: An Update

by Tea Omanovic Kolaric, Lucija Kuna, Marina Covic, Hrvoje Roguljic, Anita Matic, Renata Sikora, Marija Hefer, Ana Petrovic, Vjera Mihaljevic, Robert Smolic, Ines Bilic-Curcic, Aleksandar Vcev and Martina Smolic

Curr. Issues Mol. Biol. 2023, 45(5), 4246-4260; https://doi.org/10.3390/cimb45050270 - 11 May 2023

Cited by 2 | Viewed by 2118

Abstract

Liver fibrosis represents one of the greatest challenges in medicine. The fact that it develops with the progression of numerous diseases with high prevalence (NAFLD, viral hepatitis, etc.) makes liver fibrosis an even greater global health problem. Accordingly, it has received much attention [...] Read more.

Liver fibrosis represents one of the greatest challenges in medicine. The fact that it develops with the progression of numerous diseases with high prevalence (NAFLD, viral hepatitis, etc.) makes liver fibrosis an even greater global health problem. Accordingly, it has received much attention from numerous researchers who have developed various in vitro and in vivo models to better understand the mechanisms underlying fibrosis development. All these efforts led to the discovery of numerous agents with antifibrotic properties, with hepatic stellate cells and the extracellular matrix at the center of these pharmacotherapeutic strategies. This review focuses on the current data on numerous in vivo and in vitro models of liver fibrosis and on various pharmacotherapeutic targets in the treatment of liver fibrosis. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases, 2nd Volume)

21 pages, 900 KiB  

Open AccessReview

Non-Alcoholic Fatty Liver Disease and Bone Tissue Metabolism: Current Findings and Future Perspectives

by Oxana M. Drapkina, Anastasia Yu. Elkina, Anna F. Sheptulina and Anton R. Kiselev

Int. J. Mol. Sci. 2023, 24(9), 8445; https://doi.org/10.3390/ijms24098445 - 8 May 2023

Cited by 8 | Viewed by 3376

Abstract

Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions worldwide. Moreover, the prevalence of this liver disease is expected to increase rapidly in the near future, aligning with the rise in obesity and the aging of the population. The pathogenesis of NAFLD is [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions worldwide. Moreover, the prevalence of this liver disease is expected to increase rapidly in the near future, aligning with the rise in obesity and the aging of the population. The pathogenesis of NAFLD is considered to be complex and to include the interaction between genetic, metabolic, inflammatory, and environmental factors. It is now well documented that NAFLD is linked to the other conditions common to insulin resistance, such as abnormal lipid levels, metabolic syndrome, and type 2 diabetes mellitus. Additionally, it is considered that the insulin resistance may be one of the main mechanisms determining the disturbances in both bone tissue metabolism and skeletal muscles quality and functions in patients with NAFLD. To date, the association between NAFLD and osteoporosis has been described in several studies, though it worth noting that most of them included postmenopausal women or elderly patients and originated from Asia. However, taking into account the health and economic burdens of NAFLD, and the increasing prevalence of obesity in children and adolescents worldwide, further investigation of the relationship between osteopenia, osteoporosis and sarcopenia in NAFLD, including in young and middle-aged patients, is of great importance. In addition, this will help to justify active screening and surveillance of osteopenia and osteoporosis in patients with NAFLD. In this review, we will discuss various pathophysiological mechanisms and possible biologically active molecules that may interplay between NAFLD and bone tissue metabolism. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases, 2nd Volume)

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13 pages, 2019 KiB  

Open AccessArticle

Identification of the Interaction between Minichromosome Maintenance Proteins and the Core Protein of Hepatitis B Virus

by Kaili Du, Eriko Ohsaki, Masami Wada and Keiji Ueda

Curr. Issues Mol. Biol. 2023, 45(1), 752-764; https://doi.org/10.3390/cimb45010050 - 16 Jan 2023

Cited by 1 | Viewed by 2511

Abstract

Chronic HBV infection is a major cause of cirrhosis and hepatocellular carcinoma. Finding host factors involved in the viral life cycle and elucidating their mechanisms is essential for developing innovative strategies for treating HBV. The HBV core protein has pleiotropic roles in HBV [...] Read more.

Chronic HBV infection is a major cause of cirrhosis and hepatocellular carcinoma. Finding host factors involved in the viral life cycle and elucidating their mechanisms is essential for developing innovative strategies for treating HBV. The HBV core protein has pleiotropic roles in HBV replication; thus, finding the interactions between the core protein and host factors is important in clarifying the mechanism of viral infection and proliferation. Recent studies have revealed that core proteins are involved in cccDNA formation, transcriptional regulation, and RNA metabolism, in addition to their primary functions of capsid formation and pgRNA packaging. Here, we report the interaction of the core protein with MCMs, which have an essential role in host DNA replication. The knockdown of MCM2 led to increased viral replication during infection, suggesting that MCM2 serves as a restriction factor for HBV proliferation. This study opens the possibility of elucidating the relationship between core proteins and host factors and their function in viral proliferation. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases, 2nd Volume)

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